Objective: To define the parameters that control the uptake of macromolecules by tumor cells in culture and the factors which influence the metabolic fate of ingested macromolecules in host cells. Approach: The net uptake of radioiodinated albumin by Sarcoma S 180 and WI 38 cells in monolayer culture is measured under a variety of experimental conditions. Polycations such as basic polyamino acids and DEAE-dextran cause a marked enhancement of uptake, which increases with their molecular size. While the lower size limit (threshold of enhancement) has been defined (e.g., MW 1000 for poly-L-ornithine) the upper limits of this relationship have so far eluded investigation. The intracellular fate of ingested albumin is measured by reincubating cells in unlabeled medium and following the decrease of acid insoluble radioactivity as a function of time. The morphological correlates of these phenomena are investigated by Electron microscopy, using proteins detectable in thin sections.